“Sol-gel” processes are generally used to fabricate porous materials including self-assembled films. A sol is a liquid solution containing a colloid suspension of a material of interest dissolved in an appropriate solvent. Condensation reactions between the dissolved precursor molecules result in structures (particles, branched chains, linear chains, etc.) forming within the sol. The size, growth rate and morphology of these structures depend on the kinetics of the reactions within the solvent, which in turn are determined by parameters such as solution concentration, amount of water present, the temperature and pH of the solvent, agitation of the solvent and other parameters. Given enough time, condensation reactions will lead to the aggregation of growing particles or chains until eventually, a gel is formed. The gel can be visualized as a very large number of cross-linked precursor molecules forming a continuous, macroscopic-scale, solid phase, which encloses a continuous liquid phase consisting of the remaining solution. In the final steps of the sol-gel process, the enclosed solvent is removed (generally by drying) and the precursor molecules cross-link (a process called aging) resulting in the desired solid.
Sol-gel synthesis of materials offers several advantages over other synthetic routes. These advantages can include mild processing conditions (low temperature, low pressure, mild pH), inexpensive raw materials, no need for vacuum processing or other expensive equipment, and a high level of control over the resulting structure, particularly as it pertains to porosity. Regarding shape of the final product, there is essentially no limitation, because the liquid sol can be cast in any conceivable form before allowed to gel, including monoliths, thin films, fibers and micro- or nano-scale particles.
Porosity of materials produced in sol-gel processes can be controlled in a number of different ways. In the simplest sol-gel process, no special porogen is added to the sol and the porosity of the final solid is determined by the amount of precursor branching or aggregation before gelling. Average pore size, volume and surface area of porous sol-gel compositions increase with the size of the precursor molecules prior to the sol-gel processing.
Porosity can also be manipulated by the presence of additional materials within the solvent during the sol-gel process. The incorporation of sacrificial porogens in the sol (particularly those that can be easily removed via heating or other methods), is generally viewed as an efficient method to obtain porous solids when using sol-gel processes. Historically, these efforts were focused upon the fabrication of low dielectric constant (low-k) insulating films for the microelectronics industry. Sacrificial templates can also be used to create pores in inorganic materials formed using sol-gel processes. Sacrificial templates are usually amphiphilic molecules (i.e. those having hydrophilic and hydrophobic properties) capable of self-assembling in solution. These amphiphilic molecules create a highly-ordered structure that guides the precursor molecules to co-assemble around the structure. Once the precursor molecules co-assemble around the structure, it can be removed, leaving a negative image void.
The unique properties of self-assembling template-assisted, sol-gel compositions have generated a great deal of research. For example, in 1992, a group of researchers at Mobil Oil Corporation discovered that surfactant molecules (short amphiphilic molecules) will self-assemble in an aqueous solution of soluble silica, and upon solidification of the silica substrate, the surfactant can be removed leaving a material (called “MCM-41”) having a hexagonal honeycombed array of uniform mesopores (mesopores are those with a pore size of between about 2 and about 50 nm; see U.S. Pat. Nos. 5,057,296 and 5,102,643, which are fully incorporated by reference herein). MCM-41 is synthesized using a cationic surfactant, quaternary alkyltrimethylammonium salts and various silica sources, such as sodium silicates, tetraethyl orthosilicate, or silica gel, under hydrothermal conditions (Beck et al., 1992, J. Am. Chem. Soc. 114, 10834). The pore size of MCM-41 can be adjusted from about 1.6 nm up to about 10 nm by using different surfactants or altering synthesis conditions. Presently, template-assisted mesoporous materials are fabricated using two broad classes of self-assembling amphiphilic templates: short molecule surfactants (see Brinker et al. (Advanced materials 1999, 11 No. 7) and Kresge et al. (Nature Vol. 359 22 October 1992)) and triblock copolymers (see U.S. Pat. No. 6,592,764 which is incorporated by reference herein).
Porous materials made using sol-gel processes can be used to deliver bioactive materials. For example, Vallet-Regi et al. (Chem. Mater. 2001, 13, 308-311) described charging powdered MCM-41 with ibuprofen. In this case, the ibuprofen was loaded into MCM-41 by dissolving the ibuprofen in hexane and adding the MCM-41 compound to the hexane in a powdered form. Munoz et al. (Chem. Mater. 2003, 15 500-503) described an experiment which demonstrated that ibuprofen could be delivered at a different rate from two different formulations of MCM-41, one made using a 16 carbon surfactant and one made using a 12 carbon surfactant.
Prior to International Patent Application Number PCT/US2004/040270 (PCT '270), which is fully incorporated by reference herein, no reference described an implantable medical device or bioactive material delivery device comprising a triblock copolymer template-based sol-gel composition formed surface coating with substantially continuously interconnected channels designed to function as a bioactive material reservoir. Moreover, no reference described a triblock copolymer template-based sol-gel composition surface coating with bioactive material found within the coating itself before being applied to the surface of an implantable medical device as well as having substantially continuously interconnected channels that could further function as a bioactive material reservoir after being applied to the surface of an implantable medical device. Thus, the invention described in PCT '270 provided at least two additional mechanisms through which bioactive materials could be loaded onto the surface of an implantable medical device.
While the materials and methods described in PCT '270 provided a number of important benefits (described therein), there is still room for improvement in the creation of bioactive material carrying materials made with sol-gel processes. For instance, better control of bioactive material particles during sol-gel processing and after device implantation could provide a benefit in allowing more accurate control over the amount of bioactive materials within a particular sol-gel composition as well as more control over the release rate of bioactive materials from an implanted medical device into the physiological environment after device implantation. The present invention provides such benefits. Before describing these benefits in more detail, however, background relating to a further aspect of the present invention is described.
One challenge in the field of implantable medical devices has been adhering bioactive materials and bioactive material-containing coatings to the surfaces of implantable devices so that the bioactive materials will be released over time once the device is implanted. One approach to adhering bioactive materials to substrates, such as the surface of implantable medical devices has been to include the bioactive materials in polymeric coatings. Polymeric coatings can hold bioactive materials onto the surface of implantable medical devices, and release the bioactive materials via degradation of the polymer or diffusion into liquid or tissue (in which case the polymer is non-degradable). While polymeric coatings can be used to adhere bioactive materials to implanted medical devices, there are problems associated with their use. One problem is that adherence of a polymeric coating to a substantially different substrate, such as a stent's metallic substrate, is difficult due to differing characteristics of the materials (such as differing thermal expansion properties). Further, most inorganic solids are covered with a hydrophilic native surface oxide that is characterized by the presence of surface hydroxyl groups (M-OH, where M represents an atom of the inorganic material, such as silicon or aluminum). At ambient conditions then, at least a monolayer of adsorbed water molecules covers the surface, forming hydrogen bonds with these hydroxyl groups. Therefore, due to this water layer, hydrophobic organic polymers cannot spontaneously adhere to the surface of the implantable medical device. Furthermore, even if polymer/surface bonds (including covalent bonds) are formed under dry conditions, those bonds are susceptible to hydrolysis (i.e. breakage) upon exposure to water. This effect is particularly important in applications where devices or components containing organic/inorganic interfaces must operate in aqueous, corrosive environments such as a human or other animal's body. These difficulties associated with adhering two different material types often leads to inadequate bonding between the implantable medical device and the overlying polymeric coating which can result in the separation of the materials over time. Such separation is an exceptionally undesirable property in an implanted medical device.
Two different approaches have traditionally been followed to reinforce organic/inorganic interfaces. The first is the introduction of controlled roughness or porosity on an inorganic surface that induces polymer mechanical interlocking. The second is chemical modification of the inorganic surface via amphiphilic silane coupling agents that improve polymer wetting, bonding and interface resistance to water. While these methods provide some benefits, they are not effective in all circumstances. Thus, there is room for improvement in methods associated with adhering inorganic and organic surfaces. Certain sol-gel composition embodiments according to the present invention provide such improvements.